title: Design and synthesis of malonic acid-based inhibitors of human neutrophil collagenase (MMP8).
abstract: For most of the known synthetic inhibitors of matrix metalloproteinases (MMPs), a substrate-like binding mode was postulated on the basis of X-ray crystallographic structures of MMP/inhibitor complexes. Conversely, the malonic acid-based inhibitor (2R,S)-HONH-CO-CH(i-Bu)-CO-Ala-Gly-NH2 was found to bind in a surprisingly different manner. Using this compound as a new lead structure, the interaction sites with human neutrophil collagenase (MMP8) were optimized with a series of iteratively designed analogues and with the help of X-ray structural analysis of selected inhibitors to finally produce low molecular weight nonpeptidic compounds of 500-1000-fold improved inhibitory potency.
authors.affiliation: Max-Planck-Institut für Biochemie, Martinsried, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Graf von Roedern
authors.forename: F
authors.initials: F
authors.lastname: Grams
authors.forename: H
authors.initials: H
authors.lastname: Brandstetter
authors.forename: L
authors.initials: L
authors.lastname: Moroder
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008314:Malonates / Q000737:chemistry*; D020784:Matrix Metalloproteinase 8; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D004791:Enzyme Inhibitors; D008314:Malonates; D061965:Matrix Metalloproteinase Inhibitors; C030290:malonic acid; D020784:Matrix Metalloproteinase 8